Hypertension is a condition associated with, among other physiological problems, an increased risk of stroke, myocardial infarction, atrial fibrillation, heart failure, peripheral vascular disease and renal impairment. Despite the numerous drugs available in various pharmacological categories to treat hypertension and related physiological problems, not all patients respond to such drugs as effectively or as safely as desired. Additional therapeutic agents for the treatment of hypertension and/or related conditions are still needed.
One class of therapeutic agents reported in the literature as useful for the treatment of hypertension are inhibitors of the PDE5 enzyme (“PDE5 inhibitors”). In general, vascular endothelial cells secrete nitric oxide which acts on vascular smooth muscle cells and leads to the activation of guanylate cyclase and the accumulation of cyclic guanosine monophosphate (“cGMP”). The accumulation of cGMP causes the muscles to relax and the blood vessels to dilate, leading to a reduction in blood pressure. The cGMP is inactivated by hydrolysis to guanosine 5′-monophosphate (“GMP”) by cGMP-specific phosphodiesterases. One cGMP-phosphodiesterase involved in the inactivation of cGMP is the PDE5 enzyme. Inhibitors of the PDE5 enzyme decrease the rate of cGMP hydrolysis. This reduction in cGMP hydrolysis potentiates the actions of nitric oxide leading to a lowering of blood pressure.
Compounds that are PDE5 inhibitors have been reported in the literature. For example, WO2005049616 reports one class of pyrazolo[4,3-d]pyrimidinyl compounds. WO2005049617 reports another class of pyrazolo[4,3-d]pyrimidinyl compounds. WO2004096810 reports another class of pyrazolo[4,3-d]pyrimidinyl compounds. EP 1348707 reports another class of pyrazolo[4,3-d]pyrimidinyl compounds.
The identification of additional compounds that are PDE5 inhibitors is desirable. Such compounds can be used to treat subjects suffering from or susceptible to hypertension and/or related physiological problems and further expand the range of treatment options available for such subjects.